TAMI-27. METABOLIC MANIPULATION OF T CELLS TO TREAT BRAIN TUMORS. (12th November 2021)

• Record Type: Journal Article
• Authors: Tian, Guimei; Jin, Linchun; Doshi, Devshri; Karachi, Aida; Dajac, Mariana; Pohl-Guimaraes, Fernanda; Moore, Ginger; Rahman, Maryam; Flores, Catherine; Sarkisian, Matthew; Huang, Jianping; Mitchell, Duane; Deleyrolle, Loic
• Is Part Of: Neuro-oncology. Volume 23: Supplement 6(2021)
• Page Start: vi203
• Page End: vi204
• Publication Date: 2021-11-12
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noab196.811
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: INTRODUCTION: Glioblastoma are a challenge for neuro-oncologists and current therapies are minimally effective. Standard-of- care treatment is almost inevitably followed by disease recurrence. Adoptive T cell transfer has emerged as a viable therapeutic for brain malignancies. While promising, the efficacy of this approach is often limited by a complex immunosuppressive tumor microenvironment. These complexities mean that more sophisticated T cell products are required. OBJECTIVES: The brain tumor microenvironment provides local restraints via metabolic competition suppressing antitumor immunity, specifically inhibiting infiltration and tumoricidal functions of host and adoptively transferred tumor-reactive T cells. The overall goal of this project is to test new treatments to reverse immune dysfunction in cancer through the regulation of T cell metabolic signaling. We propose that modulating glucose pathway in T cells can potentiate their anti-tumor activity once adoptively transferred. METHODS: T cells glucose metabolic pathway was modulated via glucose transporters overexpression. The functionality of metabolically modified T cells was investigated in murine and human models. RESULTS: We demonstrated the existence of a competition for glucose between T cells and tumor cells, with tumor cells imposing glucose restriction mediating T cell hyporesponsiveness. Overexpression of glucose transporters such as Glut1 and Glut3 increased T cell glucose utilization and provide survival/growth advantage and enhanced T cell activation in glucose-restricted conditions. We also established that glucose transporter overexpression improves intratumoral infiltration of adoptively transferred T cells. CONCLUSION: This project integrates fundamental concepts of tumor and immune metabolism in the design of immunotherapy and confirms that immunometabolism represents a viable target for new cancer therapy to treat brain tumors.